June 24, 2022

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Research progress of using stem cells to produce platelets

Research progress of using stem cells to produce platelets

 

Research progress of using stem cells to produce platelets.  Various types of stem cells may produce platelets, and each type of stem cell has specific advantages and disadvantages in terms of scalability, platelet function, and other aspects.

Therefore, these must be considered in the platelet production process. Hematopoietic stem cells (HSCs) are a well-known source of traditional stem cells. However, due to their limited number, they are not widely used.

It has been proven that induced pluripotent stem cells (iPSCs), human embryonic stem cells (hESCs) and other stem cell sources can overcome the shortcomings of hematopoietic stem cells, thereby providing a new method for large-scale platelet production (see the table below).

Research progress of using stem cells to produce platelets

Therefore, researchers from the Department of Hematology Oncology, Zhongda Hospital Affiliated to Southeast University School of Medicine, and the Department of Blood Transfusion, Nanjing University School of Medicine, introduced these types of cells.

  • Hematopoietic stem cells, also known as CD34+ cells, are the simplest source of stem cells to produce platelets. Currently, hematopoietic stem cells mainly come from BM, umbilical cord blood (UCB) and peripheral blood. Compared with the other two types of cells, UCB-derived hematopoietic stem cells usually have a higher proliferation ability. However, a previous study showed that UCB-derived CD34+ cells are difficult to fully mature. One week after thrombopoietin (TPO) induction, <10% of MKs induced from UCB were determined to be polyploid. UCB’s current availability is also very limited.
  • iPSCs are produced by artificially inducing non-plurip-otent cells to express specific genes. Due to the limited availability of hematopoietic stem cells, further research on iPSCs has been launched. In the past few years, iPSCs have shown great potential in biomedical research.
  • hESCs are primitive pluripotent stem cells derived from the inner cell mass of human blastocysts. They can proliferate indefinitely in vitro, providing an ideal unlimited source for large-scale production of platelets. Over time, several methods have been developed to differentiate hESCs into MKs.
  • Adipose tissue-derived stromal cells (ASCs). With further research, more strategies for producing platelets have been designed for clinical use. ASCs are an attractive option for the production of platelets in vitro. Since ASCs contain certain basic genes that are indispensable for MK differentiation and platelet production, they can be differentiated without gene transfer

 


Gene regulation during megakaryocyte formation

MKs are considered to be the ancestors of platelets. A variety of external and internal signaling pathways are involved in the formation of megakaryocytes, but this process is ultimately carried out under the control of transcription factors, including GATA binding protein 1 (GATA-1), friends of GATA-1 (FOG-1 ), Friend Leukemia Virus Integration 1 (FLI1) and RUNT-related transcription factor 1 (RUNX1).

FLI1 is an E26 transformation specific proto-oncogene domain transcription factor. Some studies have shown that FLI1 plays an important role in megakaryocyte production, is a key regulator of megakaryocyte production, and works together with GATA-1.

The transcription factor RUNX1 plays a key role in the development of MK. For example, depletion of RUNX1 in UT-7/GM cells leads to overexpression of MK markers; however, cell proliferation is simultaneously reduced.
TribblesPseudokinase 3 gene (TRIB3) encodes a polyhedrin protein, and further studies revealed that it is involved in the regulation of cell differentiation. In primary hematopoietic cell culture, TRIB3 silencing enhanced MK differentiation. In contrast, overexpression of TRIB3 reduces the differentiation of MK.
C3G, also known as RAPGEF1, is an activator of Rap1 GTPase. It is involved in the activation of platelets and other important biological processes.

 


Promote the production of platelets

The microenvironment of platelet production. The size, hardness, matrix composition and other conditions of the BM microenvironment accurately mediate the impact of environmental factors on platelets. The three-dimensional environment expands the contact area between MKs and the surrounding environment. The production of platelets may promote the production of platelets through the interaction between platelets and the microenvironment.

The transient receptor potential cation channel subfamily V member 4, which is sensitive to ion channels, can trigger calcium influx, β1 integrin activation and internalization, and phosphorylation of human Akt to promote platelet production; this process only occurs in MKs. Attached to a softer rather than harder substrate. Experiments have shown that lysine oxidase (LOX) can adjust the hardness of the BM matrix through collagen cross-linking. Therefore, appropriate conditions, including increased LOX levels and softer substrates, are conducive to platelet production.

The interaction between progenitor cells and blood vessels is crucial before blood cells are released in the circulation. In order to simulate the vascular network, a customized perfu-sion chamber containing a multi-channel freeze-dried silk sponge was constructed, which effectively increased the production of platelets.

Different inducers of platelet production. The factors most widely used to promote platelet production include interleukin-3 (IL-3), IL-6, IL-9, IL-11 and TPO.

IL-3, IL-6, IL-9 and IL-11 indirectly affect the production of MK induced by TPO. In vitro experiments have shown that adding the above-mentioned mixed cytokines can stimulate the production of platelets. IL-3 and TPO have a synergistic effect in promoting the differentiation of MK. In an inflammatory state, IL-6 promotes platelet formation by increasing the level of TPO. In the early stages of MK differentiation, stem cell factors also play an important role in promoting cell proliferation.

TPO is a major regulator of platelet production, mainly produced by hepatocytes in serum. TPO combines with Mpl to regulate the differentiation, development, maintenance and proliferation of hematopoietic stem cells and MK. When the number of platelets decreases, the level of free TPO in plasma increases, which stimulates the differentiation of hematopoietic progenitor cells in BM into MK lines to produce more platelets

Romibustine is a synthetic peptide that binds to TPO-R on MKs to activate downward signals and stimulate platelet production. A multicenter study on romiplostim for the treatment of chemotherapy-induced thrombocytopenia was conducted in solid tumors and hematological malignancies; the results showed that 71% of patients responded to romiplostim, and weekly dosing was considered better than intra-cycle dosing. The analysis of five clinical trials proved that self-administration of romiplostim can achieve 95% of the response, and there are no adverse reactions.

 

Conclusion

Finally, the author believes that significant progress has been made in the use of stem cells to produce platelets, and this field is developing steadily.

Different stem cell sources show specific characteristics, so the most suitable source can be selected according to various requirements.

Research on gene regulation, production microenvironmental conditions and inducing factors may help provide more insights.

Further progress must be made in platelet production to meet clinical requirements. More readily available sources of stem cells, large-scale in vitro platelet production, more effective inducing factors and various other issues remain unsolved.

However, despite these challenges, continuous breakthroughs and developments may overcome these obstacles and achieve the ultimate goal, which will hopefully extend the life of more patients requiring platelet transfusion.

 

(sourceinternet, reference only)


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